AUSTIN, Texas—An examination of gene expression in the frontal cortex has found that brain function is even more impaired in alcoholics with cirrhosis of the liver, one of the most common and serious medical complications linked to alcoholism.

Sustained exposure to alcohol can cause scarring and dysfunction of the liver, referred to as cirrhosis. Heavy alcohol use can also cause brain damage.

A recent study by Dr. R. Dayne Mayfield and colleagues found that cirrhotic alcoholics appear to have more impaired brain function than non-cirrhotic alcoholics.

Their results are published in the September issue of Alcoholism: Clinical & Experimental Research.

"The liver's main function is to remove poisons from the blood," explained Mayfield, a research scientist at the Waggoner Center for Alcohol and Addiction Research at The University of Texas at Austin. "It also helps the body absorb certain nutrients like fats and fat-soluble vitamins. You cannot live without a functioning liver."

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Mayfield is the corresponding author for the study.

He added that about 10 to 20 percent of heavy drinkers develop cirrhosis. It is the seventh leading cause of death among young and middle-aged adults in the United States. About 10,000 to 24,000 deaths from cirrhosis each year may be due to alcohol consumption.

"Cirrhotic patients [have] dysfunctional livers that cannot remove poisons from the blood stream," Mayfield said. These poisons are able to move into the brain and disrupt normal function.

"When a gene or deoxyribonucleic acid (DNA) is 'turned on,'" said Mayfield, "it serves as a template for synthesis of ribonucleic acid (RNA), which in turn produces protein, the key element in cell function. These 'genes' hold the key or code for the ultimate production of proteins that control all functions of the brain. We know that heavy alcohol drinking changes the regulation of genes in the brain. We predicted that alcohol-related changes in brain genes would be magnified in alcoholics with cirrhosis."

Researchers obtained brain samples from the Brisbane Node of the National Health & Medical Research Council Brain Bank and the Tissue Resource Centre at the University of Sydney, Australia. They compared roughly 47,000 element cDNA microarrays taken from two groups: seven cirrhotic and 14 non-cirrhotic alcoholic cases.

"We found that the levels of many important brain genes changed in the cirrhotic patients," said Mayfield. "These genes are important in regulating cell death and how individual cells in the brain talk to each other in a meaningful way."

"The level of gene expression differed significantly between tissue from cirrhotic and non-cirrhotic alcoholics," added John H. Krystal, the Robert L. McNeil, Jr. professor of clinical pharmacology and deputy chairman for research in the Department of Psychiatry at Yale University School of Medicine and the VA Connecticut Healthcare System. "Out of 1,125 genes, 482 genes showed increased expression and 643 genes showed reduced expression in the cirrhotic individuals. With the levels of so many genes changing, this study suggests widespread effects in many cellular pathways related to cirrhosis in the alcoholic group."

More specifically, those genes involved in neurite growth, neuronal cell adhesion and synaptic transmission showed greater inhibition at the mRNA level among the alcoholic cases.

"Cells in the brain have to maintain connections in order to operate," explained Mayfield. "This is similar to the way the Internet works to transmit information across the globe. The Internet would slow down or stop if enough connections are interrupted or changed. Similarly, the genes outlined above are responsible for proper connections and communication between cells in the brain. Without them, normal function would not be possible."

Both Mayfield and Krystal said the central message of the study is that alcoholism, especially when accompanied by a serious medical complication such as cirrhosis of the liver, can produce widespread changes in the body and brain.

"One hopes that a better understanding of the cellular processes related to the destructive impact of alcoholism upon the brain may help to guide the development of treatments that might protect people from neural damage related to alcoholism, and help them to recover from alcoholism," said Krystal. "Important questions are: 'How reversible are the changes in gene expression in the brain when alcoholics stop drinking?' and 'How dependent is the recovery of the brain upon the recovery of the liver?'"

For more information contact: R. Dayne Mayfield, Ph.D., The University of Texas at Austin, 512-232-2512; John H. Krystal, M.D., Yale University School of Medicine, 203-937-4790.